Single-Cell Analyses Identify Dysfunctional CD16(+) CD8 T Cells in Smokers

Tobacco smoke exposure contributes to the global burden of communicable and chronic diseases. To identify the immune cells affected by smoking, we use single-cell RNA sequencing on peripheral blood from smokers and nonsmokers. Transcriptomes reveal a subpopulation of FCGR3A (CD16)-expressing natural killer (NK)-like CD8 T lymphocytes that increase in smokers. Mass cytometry confirms elevated CD16(+) CD8 T cells in smokers. Inferred as highly differentiated by pseudotime analysis, NK-like CD8 T cells express markers that are characteristic of effector memory re-expressing CD45RA T (T(EMRA)) cells. Indicative of immune aging, smokers’ CD8 T cells are biased toward differentiated cells, and smokers have fewer naive cells than nonsmokers. DNA methylation-based models show that smoking dose is associated with accelerated aging and decreased telomere length, a biomarker of T cell senescence. Immune aging accompanies T cell senescence, which can ultimately lead to impaired immune function. This suggests a role for smoking-induced, senescence-associated immune dysregulation in smoking-mediated pathologies.